Paliouras, AR, Buzzetti, M, Shi, L, Donaldson, IJ, Magee, P, Sahoo, S, Leong, H, Fassan, M, Carter, M, Di Leva, G ORCID: https://orcid.org/0000-0001-6759-8682, Krebs, MG, Blackhall, F, Lovly, CM and Garofalo, M (2020) Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition. EMBO Molecular Medicine.

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Abstract

A subset of lung adenocarcinomas is driven by the EML4‐ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on‐target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4‐ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti‐apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first‐, second‐ and third‐generation ALK inhibitors.

Item Type: Article
Additional Information: This is the final published version (version of record). It was first published online via Wiley at https://doi.org/10.15252/emmm.201911099 - please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Depositing User: Symplectic
Date Deposited: 19 Jun 2020 09:26
Last Modified: 19 Jun 2020 09:27
URI: https://eprints.keele.ac.uk/id/eprint/8225

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